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Hemicholinium-3 prevents the working memory impairments and the cholinergic hypofunction induced by ethylcholine
J J Chrobak1, M J Spates, R W Stackman
1Department of Psychology, Rutgers University, New Brunswick, NJ 08903.
Insights
Intraventricular ethylcholine aziridinium ion (AF64A) impairs memory by reducing high affinity choline transport (HAChT). Pretreatment with hemicholinium-3 (HC-3) prevented these memory deficits and neurochemical changes.
Area of Science:
- Neuroscience
- Neuropharmacology
- Cognitive Science
Background:
- Acetylcholine is crucial for memory and cognitive functions.
- Ethylcholine aziridinium ion (AF64A) is a neurotoxin that selectively damages cholinergic neurons.
- High affinity choline transport (HAChT) is a key mechanism for acetylcholine synthesis.
Purpose of the Study:
- To investigate if hemicholinium-3 (HC-3), a HAChT inhibitor, can prevent AF64A-induced memory impairments.
- To determine if AF64A's effects on memory are mediated by its interaction with HAChT.
- To assess the role of septohippocampal cholinergic activity in working memory.
Main Methods:
- Rats were trained on a radial arm maze (RAM) task with a delay.
- Animals received intraventricular injections of AF64A, or AF64A preceded by HC-3.
- Behavioral performance (RAM task) and hippocampal HAChT levels were measured.
Main Results:
- AF64A administration significantly impaired RAM task performance and reduced hippocampal HAChT by 32%.
- Rats pretreated with HC-3 showed no significant memory deficits or decrease in HAChT.
- These results suggest AF64A's cholinotoxicity is linked to HAChT inhibition.
Conclusions:
- Memory deficits induced by AF64A are a direct result of its cholinotoxic effects on HAChT.
- Blocking HAChT with HC-3 protects against AF64A-induced memory impairment.
- Alterations in septohippocampal cholinergic activity significantly disrupt working memory.
Abstract:
The present study examined whether intraventricular administration of the potent high affinity choline transport (HAChT) inhibitor hemicholinium-3 (HC-3) would attenuate the memory impairments and the neurochemical deficits induced by i.c.v. ethylcholine aziridinium ion (AF64A). Male Sprague-Dawley rats were trained to perform a delayed-non-match to sample radial arm maze (RAM) task in which a 1-h delay was imposed between the fourth and fifth arm selections. Following 30 acquisition trials, animals were bilaterally injected with AF64A (3 nmol/side) or AF64A preceded by HC-3 (20 micrograms/side) into the lateral ventricles and allowed 7 days to recover before behavioral testing resumed. Control animals received either artificial cerebrospinal fluid or HC-3. AF64A-treated rats were significantly impaired in their performance of the RAM task as evidenced by fewer correct choices following the delay and more total errors to complete the task. This behavioral deficit was associated with a significant (32%) decrease in HAChT in the hippocampus. In contrast, animals pretreated with HC-3 exhibited no significant decreases in HAChT or decrements in RAM performance. These findings indicate that the memory deficits resulting from intraventricular administration of AF64A are a consequence of the compound's cholinotoxic properties and in particular its interaction with the HAChT carrier. Furthermore they demonstrate that a select alteration of septohippocampal cholinergic activity is sufficient to disrupt working memory processes.